Fight Aging! Newsletter, March 23rd 2020

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,
please visit:

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more:


  • Splicing Regulation and Naked Mole-Rat Longevity
  • Failing Mitophagy in the Aging Heart
  • Mild Depolarization of the Mitochondrial Membrane as a Mechanism of Slowed Aging in Long-Lived Mammals
  • Mapping p16 and p21 Markers of Cellular Senescence in Humans by Tissue and Age
  • The Two Way Relationship Between Cellular Senescence and Cancer in Bone Marrow
  • HNF4α in the Effects of Intermittent Fasting on the Liver
  • TREM2 Antibodies as an Immunotherapy for Alzheimer’s Disease
  • Amyloid-β as a Contributing Cause of Age-Related Cardiovascular Disease
  • A Mechanism by Which Obesity Contributes to Hypertension
  • Quantifying the Effects of a Healthy Lifestyle on Later Risk of Age-Related Disease
  • A Survey of Common Risk Factors and their Effects on Life Expectancy
  • The Proteomic Effects of Cardiopoietic Stem Cell Therapy Following Heart Attack
  • Reduced Calorie Intake and Periodic Fasting Independently Contribute to the Benefits of Calorie Restriction
  • MicroRNAs miR-21 and miR-217 are Important in the Spread of Cellular Senescence via Cell Signaling
  • Failing Mitochondrial Quality Control with Age Considered in Terms of Inter-Organelle Contact Sites

Splicing Regulation and Naked Mole-Rat Longevity

Multiple proteins can be assembled from the blueprint of a any given gene, depending on which of the intron sequences (usually removed) and exon sequences (usually retained) within the overall gene sequence are included in the final protein. Splicing is the part of the gene expression process that determines this outcome, and regulation of splicing is one of the many aspects of cellular biochemistry that becomes disarrayed with age. It is an open question as to how important this is versus other processes in aging, as well as how far downstream from the root causes of aging splicing dysfunction might be, but splicing changes might be relevant in the pace of creation of senescent cells, to pick one example.

Naked mole-rats are exceptionally long-lived for their size as rodents, and by comparing their biochemistry to that of similarly sized mice, researchers have found a range of mechanisms that might contribute to this longevity. Naked mole-rats exhibit very good DNA repair; naked mole-rat senescent cells do not secrete damaging and inflammatory signals; cancer suppression mechanisms are very effective; and so forth. Researchers here add stability of splicing regulation to the list. Naked mole-rats do not exhibit the age-related changes in splicing factor expression observed in other mammals, and splicing thus remains stable throughout most of life.

Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation

Naked mole-rats (NMRs) have amongst the longest lifespans relative to body size of any known, non-volant mammalian species. They also display an enhanced stress resistance phenotype, negligible senescence and very rarely are they burdened with chronic age-related diseases. Alternative splicing (AS) dysregulation is emerging as a potential driver of senescence and ageing. We hypothesised that the expression of splicing factors, important regulators of patterns of AS, may differ in NMRs when compared to other species with relatively shorter lifespans.

We designed assays specific to NMR splicing regulatory factors and also to a panel of pre-selected brain-expressed genes known to demonstrate senescence-related alterations in AS in other species, and measured age-related changes in the transcript expression levels of these using embryonic and neonatal developmental stages through to extreme old age in NMR brain samples. We also compared splicing factor expression in both young mouse and NMR spleen and brain samples. Both NMR tissues showed approximately double the expression levels observed in tissues from similarly sized mice. Furthermore, contrary to observations in other species, following a brief period of labile expression in early life stages, adult NMR splicing factors and patterns of AS for functionally relevant brain genes remained remarkably stable for at least two decades.

These findings are consistent with a model whereby the conservation of splicing regulation and stable patterns of AS may contribute to better molecular stress responses and the avoidance of senescence in NMRs, contributing to their exceptional lifespan and prolonged healthspan.

Failing Mitophagy in the Aging Heart

Every cell contains hundreds of mitochondria, bacteria-like organelles that work to provide the cell with adenosine triphosphate (ATP), a chemical energy store molecule to power cellular biochemistry. With age, mitochondrial function falters throughout the body. This may be largely a consequence of failing mitophagy, a form of the cellular maintenance process of autophagy that is responsible for destroying worn and damaged mitochondria. In tissues with high energy demands, such as the heart, this loss of function is a sizable contributing factor in the development of age-related disease.

At present the research and development communities are still in the comparatively early stages in the production of ways to address this problem. Both upregulation of NAD+ in mitochondria and delivery of mitochondrially targeted antioxidants appear to somewhat reverse the loss of mitophagy, and thus improve mitochondrial function, but the outcomes in human trials and animal models are not reliably positive at this point in time. The effect size of these treatments is likely not large enough. A range of better approaches lie ahead, such as periodic delivery of large numbers of whole mitochondria harvested from cell cultures, but even these classes of treatment do not address the root causes of mitochondrial decline.

Researchers have identified a number of proteins important to mitophagy wherein expression changes with age, but connecting these changes to the underlying damage that causes aging is yet to be accomplished. Repairing forms of molecular damage known to cause aging and observing the results in mitochondria is probably a faster strategy than trying to work backwards from the present understanding of disrupted regulation of mitophagy. This sort of approach could be carried out today for clearance of senescent cells, and some forms of stem cell transplantation, but most forms of cell and tissue damage thought to cause aging still require potential therapies to be further developed.

The Aging Heart: Mitophagy at the Center of Rejuvenation

Aging is associated with structural and functional changes in the heart and is a major risk factor in developing cardiovascular disease. Many recent studies have focused on increasing our understanding of the basis of aging at the cellular and molecular levels in various tissues, including the heart. It is known that there is an age-related decline in cellular quality control pathways such as autophagy and mitophagy, which leads to accumulation of potentially harmful cellular components in cardiac myocytes.

A growing body of data support the anti-aging effects of enhanced autophagy. Many studies have demonstrated that enhancing autophagy by limiting caloric intake, genetic manipulation, or pharmacological treatments increases lifespan in various organisms. For instance, transgenic mice with systemic overexpression of Atg5 have enhanced autophagic activity in tissues which leads to health benefits such as reduced weight gain with age and extended life spans compared to wild type mice.

The cardioprotective effects of enhanced autophagy during the aging process were recently confirmed, who developed a Becn1 knock-in mouse model with constitutively increased basal autophagy due to a disruption in the Bcl-2 binding to Becn1. They found that health and life spans are significantly increased in the knock-in mice. Moreover, aged Becn1 knock-in mice have reduced cardiac hypertrophy and interstitial fibrosis compared to aged-matched wild type mice, confirming that preserving autophagy in the heart delays or even prevents cardiac aging.

In summary, declines in autophagy and mitophagy in tissues clearly play a role in the aging process and contribute to development of age-related diseases. The main questions that remain unanswered include: why are autophagy and mitophagy suppressed with age and can these pathways be restored in the aged heart? Relatively little is still known about the molecular mechanism underlying the decrease in autophagy and mitophagy and whether there are tissue specific differences. Although manipulation of autophagy and mitophagy pathways are protective in pre-clinical models, the level of activity must be carefully monitored as excessive autophagy can lead to excessive degradation of key cellular components. Increased knowledge into how these pathways are regulated as well as altered with age will allow for more specific manipulation. Further understanding will also provide important insights into how future therapies can protect the heart against age-specific functional decline.

Mild Depolarization of the Mitochondrial Membrane as a Mechanism of Slowed Aging in Long-Lived Mammals

Every cell contains hundreds of mitochondria, cell structures that evolved long ago from symbiotic bacteria. They carry remnants of the original bacterial DNA, and continually fuse and divide like bacteria. Mitochondria participate in many core cellular processes, but arguably their most important function is to produce the chemical energy store molecule adenosine triphosphate (ATP), needed to keep the cell running. This is an energetic process, and produces free radicals such as reactive oxygen species (ROS) as a side-effect. ROS damage cellular machinery, provoking the activity of repair mechanisms. This damage is actually used as a signal, such as when it triggers the beneficial response to exercise: mitochondria work harder, moderately more ROS is generated, and muscle cells have evolved to repair and build tissue in response.

Too much ROS, too great a level of oxidative damage, is harmful, however. It overwhelms repair and maintenance mechanisms, giving rise to the state of oxidative stress. This is characteristic of old tissues and age-related disease, and early theories of aging focused strongly on oxidative damage as a primary mechanism by which aging leads to age-related disease. The picture is more nuanced than this, however, and where oxidative stress falls in the chain of first causes and downstream consequences continues to be debated.

In today’s open access research, scientists point out certain aspects of mitochondrial biochemistry that might contribute to the exceptional longevity of bats and naked mole-rats in comparison to mice and other similarly sized mammals. The mitochondria of naked mole-rats and bats preserve a mild depolarization response that minimizes ROS production, and they do this more effectively than mice. It is possible to argue that in the case of bats the metabolic demands of flight, and in the case of naked mole-rats oxygen-poor underground environments, have led to mitochondria that are more resilient to processes of aging. It is still hard to pick out what is cause and what is consequence, however, and it is hard to assess affect size in terms of the degree to which exceptional species longevity results from one mechanism versus another mechanism. Mitochondria are only one of a number of mechanisms of longevity studied in naked mole-rats, and relative contributions are debated.

Newly confirmed biochemical mechanism in mouse, bat and naked mole rat cells is a key component of the anti-ageing program

Naked mole rats, an east African rodent of a size comparable to moles or mice, show a strongly delayed process of ageing and live up to 30 years. Scientists now confirmed a mechanism in mouse, bat and naked mole rat cells – a “mild depolarization” of the inner mitochondrial membrane – that is linked to ageing: Mild depolarization regulates the creation of mitochondrial reactive oxygen species (mROS) in cells and is therefore a mechanism of the anti-ageing program. In mice, this mechanism falls apart at the age of 1 year, while in naked mole rats this does not occur until ages of up to 20 years.

Mitochondrial reactive oxygen species (mROS) such as hydrogen peroxide are by-products of cell respiration and, in higher doses, associated with various diseases and ageing processes. There are different mechanisms at the inner and outer mitochondrial membranes that regulate the mROS production. Key function of cell respiration is energy production in the form of ATP (adenosine triphosphate) through coupling of mitochondrial respiratory chain complexes with ATP synthase. Different mitochondrial intermembrane space enzymes (hexokinases I + II and creatine kinase) have now been confirmed to slightly lower the membrane potential of the inner mitochondrial membrane (“mild depolarization”). This means that the differences in the electric load between the inner and the outer space of the mitochondria are lowered and the energy production through ATP synthesis is reduced to some extent. At the same time this leads to the cessation of mROS production.

The research team was able to show that both biochemical mechanisms do not operate in the same intensity and efficiency in different species and tissues and at different ages: The researchers examined the hexokinases I + II and creatine kinase mechanisms in various tissues (lung, kidney, brain, skeletal muscles, heart, and others) in mice (Mus musculus), naked mole rats (Heterocephalus glaber), and Seba’s short-tailed bats (Carollia perspicillata). They found interesting differences: Mild depolarization significantly starts decreasing after 1 year of age in mice with negligible levels after 24 months in skeletal muscles, diaphragm, heart, brain, and spleen. In lung and kidney tissue, mild depolarization decreases to a lesser extent with ageing. “The crumbling of the anti-ageing program in the cells starts after only a third of the average life span in mice, while the naked mole rats and Seba’s short-tailed bats maintain mild depolarisation and hence the suppression of mROS production up to high ages. This contributes to the extraordinary longevity of these species.”

Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program

The mitochondria of various tissues from mice, naked mole rats (NMRs), and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species (mROS): hexokinases I and II and creatine kinase bound to mitochondrial membranes. Both systems operate in a manner such that one of the kinase substrates (mitochondrial ATP) is electrophoretically transported by the ATP/ADP antiporter to the catalytic site of bound hexokinase or bound creatine kinase without ATP dilution in the cytosol.

One of the kinase reaction products, ADP, is transported back to the mitochondrial matrix via the antiporter, again through an electrophoretic process without cytosol dilution. The system in question continuously supports H+-ATP synthase with ADP until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level (i.e., mild depolarization of mitochondria). This ∆ψ decrease is sufficient to completely inhibit mROS generation.

In 2.5-y-old mice, mild depolarization disappears in the skeletal muscles, diaphragm, heart, spleen, and brain and partially in the lung and kidney. This age-dependent decrease in the levels of bound kinases is not observed in NMRs and bats for many years. As a result, ROS-mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived NMRs and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system.

Mapping p16 and p21 Markers of Cellular Senescence in Humans by Tissue and Age

In that part of the research community focused on the role of cellular senescence in aging, the consensus is that the markers presently used to identify senescent cells are placeholders waiting for a better approach. They are not sufficiently universal. Senescent cells might be different enough in different tissues to require tissue specific approaches to assess their presence to a usefully exact degree.

This point is illustrated by the results of a recent survey of p16 and p21 in humans by tissue type and age. That neither p16 nor p21 expressing cells increased in number with age in lung tissue strongly suggests that senescent cells in lungs are meaningfully different from those elsewhere in the body, at least in this aspect of their biochemistry. Humans should certainly be expected to have an increase in senescent cells in the lungs, as in all tissues, with advancing age. The same argument applies to the apparent absence of p16 and p21 expressing cells in muscle.

Why do we want reasonably accurate measures of senescent cell burdens by tissue? Because this will be needed as a part of the development and validation of senolytic therapies capable of selectively destroying senescent cells. Early programs are getting by with the existing markers, but as the myriad age-related diseases that can be turned back via senolytic treatments are explored in greater depth, better assays will be needed. In clinical practice, people will want an assessment of senescence burden, not just symptoms, as a way to decide when to apply treatments prior to the development of significant dysfunction. These are important considerations, and the present markers are just not up to the task.

Survey of senescent cell markers with age in human tissues

Cellular senescence, triggered by sublethal damage, is characterized by indefinite growth arrest, altered gene expression patterns, and a senescence-associated secretory phenotype. While the accumulation of senescent cells during aging decreases tissue function and promotes many age-related diseases, at present there is no universal marker to detect senescent cells in tissues.

Cyclin-dependent kinase inhibitors 2A (p16/CDKN2A) and 1A (p21/CDKN1A) can identify senescent cells, but few studies have examined the numbers of cells expressing these markers in different organs as a function of age. Here, we investigated systematically p16- and p21-positive cells in tissue arrays designed to include normal organs from persons across a broad spectrum of ages.

Increased numbers of p21-positive and p16-positive cells with donor age were found in skin (epidermis), pancreas, and kidney, while p16-expressing cells increased in brain cortex, liver, spleen, and intestine (colon), and p21-expressing cells increased in skin (dermis). The numbers of cells expressing p16 or p21 in lung did not change with age, and muscle did not appear to have p21- or p16-positive cells. In summary, different organs display different levels of the senescent proteins p16 and p21 as a function of age across the human life span.

The Two Way Relationship Between Cellular Senescence and Cancer in Bone Marrow

Cells become senescent in response to a variety of circumstances. The vast majority are cases of replicative senescence, somatic cells reaching the Hayflick limit. Cell damage and toxic environments also produce senescence, and senescent cells are also created as a part of the wound healing process. A senescent cell ceases replication and begins to secrete inflammatory and pro-growth signals, altering the nearby extracellular matrix and behavior of surrounding cells – even encouraging them to become senescent as well.

Near all senescent cells last a short time only, as they self-destruct or are removed by the immune system. When the presence of senescent cells is transient, their signals are a useful part of the processes of regeneration following injury. Cellular senescence also serves to lower the risk of cancer, ensuring that cells with significant DNA damage (or that might gain significant DNA damage due to a locally genotoxic environment) are prevented from replication. Senescent cells linger with age, however. In older tissues they last longer and are created in greater numbers, and their signals become very harmful when present for the long term. In this way, cellular senescence is an important cause of aging.

While compelling evidence has existed for decades for the accumulation of senescent cells to be a contributing cause of aging, this area of study has only comparatively recently found acceptance and significant funding. A decade ago near all work on senescent cells took place in the context of cancer, carried out by researchers who didn’t think that senescence was all that relevant to aging at all. Cancers generate senescent cells by their very nature, and there is a complex relationship between cellular senescence and cancerous tissues. Senescence is an initially protective mechanism when the number of cells (cancerous and senescent) is small, locking down replication and summoning immune cells. Given established cancer tissue, or the burden of senescent cells in old tissues, then the inflammatory, pro-growth signaling of senescent cells instead encourages cancer growth and spread. Some cancers, particularly leukemias, even appear to aggressively generate more senescent cells in order to accelerate their growth.

Bone Marrow Senescence and the Microenvironment of Hematological Malignancies

Bone marrow (BM) disorders, including myeloproliferative neoplasm (MPN), myelodysplastic syndrome (MDS), leukemia, and multiple myeloma are largely diseases of the elderly and as our population ages their incidence will likely continue to increase and with it, disease associated mortality. Acute myeloid leukemia (AML), alone accounted for 85,000 deaths globally in 2016 and multiple myeloma caused 98,000 deaths. Hematopoietic malignancies including AML multiple myeloma, MPNs, and MDS are highly dependent on the bone marrow microenvironment for survival.

The BM is the primary hematopoietic organ in adults. It comprises of blood vessels, nerve tissue, and a heterogeneous population of cells that are either directly involved in the generation of blood cells or support the hematopoietic function of the tissue. Together, all the components of the BM tightly regulate normal hematopoiesis to ensure adequate production of mature blood cells. In blood cancers, however, this process is disrupted resulting in cytopenias and immunosuppression. In AML, this is thought to be instigated by leukemic cells directly blocking differentiation of normal hematopoietic stem cells (HSC), as well as the manipulation of other BM-derived cells (including macrophages, endothelial cells, fibroblasts, and adipocytes).

Cellular senescence is the irreversible arrest of cell proliferation. It is associated with the secretion of numerous pro-inflammatory cytokines, chemokines, proteases, and growth factors, known as the senescence-associated secretory phenotype (SASP). It occurs as a response to cellular damage and is thought to have evolved to both suppress development of cancer and to promote tissue repair and wound healing. In the short term the SASP plays an important role in recruiting immune cells to sites of cellular damage in order to promote tissue repair, limit tissue fibrosis, and clear senescent cells. However, it appears that this process becomes less effective with age and senescent cells gradually accumulate. Overall the senescent response becomes maladaptive and there is now increasing evidence that it contributes to a number of age-related phenotypes and pathologies. When it persists over time the SASP has paradoxically been shown to disrupt a number of cellular and tissue functions to create a pro-tumoral and chemotherapy-resistant environment.

Age related changes within the BM microenvironment contribute to the development of hematological malignancies. These changes can also affect disease progression and response to treatment, and this may contribute, for example, to poorer outcomes observed in older patients with AML, which are not sufficiently explained by the differences in adverse prognostic features. AML cells were shown to induce a senescent phenotype in BM stromal cells (BMSCs) resulting in the secretion of a SASP which supports the survival and proliferation of leukemic blasts. In vivo experiments, using the p16-3MR model of senescence, showed that leukemic blast derived superoxide induces p16INK4A driven senescence in BMSCs and that deletion of these senescent BMSCs slows tumor progression and prolongs animal survival.

As another example multiple myeloma cells have been shown to induce a SASP and senescence in mesenchymal stem cells which creates an environment that supports myeloma cells growth, although the exact relationship between the myeloma cells and the senescent mesenchymal stem cells remains to be explored further. However, as with a number of solid tumors it is becoming increasingly clear that a senescent microenvironment favors survival of malignant cells in the bone marrow. It remains yet to be determined whether an existing senescent environment, as is observed with increasing age, drives the development of these malignancies or whether in fact the expansion of clonal cell populations within the bone marrow microenvironment drives the senescent process, accelerates aging and impairs immunosurveillance and clearance of both senescent cells and pre-malignant cells. It is also possible that these two processes together create the senescent BM microenvironment that is observed both with increasing age and in BM malignancies.

However, as there is increasing evidence that senescence in the bone marrow microenvironment forms a fundamental part of the malignant phenotype, this raises the question whether targeting the “benign” senescent cells in the BM microenvironment could disrupt the supportive nature of the tumor microenvironment and as a result impair tumor survival.

HNF4α in the Effects of Intermittent Fasting on the Liver

Intermittent fasting strategies such as alternate day fasting are known to be beneficial to health in humans and both health and longevity in animal models. A portion of this outcome likely stems from some degree of reduction in overall calorie intake, but animal studies in which calorie intake is consistent between control and intermittent fasting groups demonstrate that benefits still arise even when calories are not reduced. Lengthy enough periods of hunger likely trigger the same cellular maintenance mechanisms as play a role in the metabolic response to calorie restriction when practiced without fasting. The biochemistry of this response is enormously complex, however. Near everything in cellular metabolism is affected, often in different ways in different organs, and thus even after decades of research, the scientific community is still finding new mechanisms to explore.

In experiments with mice, researchers identified how every-other-day fasting affected proteins in the liver, showing unexpected impact on fatty acid metabolism and the surprising role played by a master regulator protein that controls many biological pathways in the liver and other organs. In particular, the researchers found that the HNF4α protein, which regulates a large number of liver genes, plays a previously unknown role during intermittent fasting.

“For the first time we showed that HNF4α is inhibited during intermittent fasting. This has downstream consequences, such as lowering the abundance of blood proteins in inflammation or affecting bile synthesis. This helps explain some of the previously known facts about intermittent fasting.” The researchers also found that every-other-day-fasting – where no food was consumed on alternate days – changed the metabolism of fatty acids in the liver, knowledge that could be applied to improvements in glucose tolerance and the regulation of diabetes.

“What’s really exciting is that this new knowledge about the role of HNF4α means it could be possible to mimic some of the effects of intermittent fasting through the development of liver-specific HNF4α regulators.”

TREM2 Antibodies as an Immunotherapy for Alzheimer’s Disease

Researchers here report on preliminary evidence that antibodies binding to TREM2 can enhance the ability of the immune cells known as microglia to clear out debris and metabolic waste in brain, particularly the amyloid-β plaques thought to contribute to the progression of the condition. Given the unremitting record of failure to date for amyloid-β clearance approaches to produce material benefits in patients, it is something of a question as to whether more and better clearance is what is needed right now. From a reductionist point of view, amyloid-β aggregates should indeed be removed, as their presence is a material difference between old and young brains. That doesn’t mean that amyloid-β is necessarily the primary driver of the disease state, however. Perhaps its contribution will only become clear once the other pathologies of Alzheimer’s disease have been addressed: neuroinflammation, tau aggregates, and vascular dysfunction.

Researchers have identified a specific antibody that binds to the brain’s immune cells, termed “microglia”. This stimulates their activity in such a way that they live longer, divide more quickly and detect aberrant substances more easily. In mice with disease symptoms resembling those of Alzheimer’s, studies revealed that deposits of proteins (called “plaques”) were recognized and degraded more quickly. The notorious plaques are among the hallmarks of Alzheimer’s disease, and are suspected to cause neuronal damage.

The research focuses on TREM2, a so-called receptor on the cell surface to which other molecules can attach. TREM2 can occur in different versions from person to person – some of these altered versions drastically increase the risk of developing Alzheimer’s in old age. In previous studies, researchers found that these special variants put the microglia into an irreversible dormant state, which prevents the immune cells from functioning properly to recognize, absorb and break down plaques and dead cells. “Conversely, we suspect that activation of the microglia could help to eliminate plaques and thus combat Alzheimer’s. TREM2 seems to play an important role in this process. The receptor apparently helps to switch the microglia from dormant to active mode.”

This is precisely the approach the team are pursuing. The antibody identified, which is now generated using biotechnological methods, binds to TREM2, thereby triggering processes that enhance microglia activity. However, the researchers cautioned that further studies are required prior to progressing this approach to clinical trials: “We have shown that immune cells can be stimulated to break down amyloid deposits more effectively. This demonstrates that our approach can work in principle. However, there is still a long way to go before it can be tested in humans and additional data is necessary to validate this approach.”

Amyloid-β as a Contributing Cause of Age-Related Cardiovascular Disease

Amyloid-β is one of the few proteins in the human body capable of misfolding in a way that encourages aggregation, causing the misfolded version to spread and form harmful deposits in tissues. This process is best known in the context of Alzheimer’s disease, where an active debate continues over whether it is actually an important part of the condition or a side-effect of other important mechanisms. Amyloid-β aggregation also occurs in the cardiovascular system, however. There is some evidence for the presence of amyloid-β in brain and vasculature to be in a state of dynamic equilibrium, but equally the disease processes that arise in these two locations might still be largely independent of one another.

Aging-related cellular and molecular processes including low-grade inflammation are major players in the pathogenesis of cardiovascular disease (CVD) and Alzheimer’s disease (AD). Epidemiological studies report an independent interaction between the development of dementia and the incidence of CVD in several populations, suggesting the presence of overlapping molecular mechanisms. Accumulating experimental and clinical evidence suggests that amyloid-beta (Aβ) peptides may function as a link among aging, CVD, and AD.

Experimental evidence indicates that Aβ peptides may be actively involved in downstream pathways leading to plaque rupture, thrombosis, and subsequent clinical manifestations of the acute coronary syndrome (ACS). Αβ1-40 stimulates platelet activation and adhesion in humans and mice and induces release of matrix metalloproteinases by human monocytes to increase plaque vulnerability. Although patients with coronary artery disease (CAD) are more likely to develop AD-like neuropathological lesions than those without CAD, whether atherogenesis occurs in parallel or independently from brain parenchyma amyloid load in humans is unknown.

A pathophysiological role of Aβ1-40 across the continuum of cardiovascular disease is suggested through its independent association with a broad spectrum of vascular and cardiac involvement from early functional vascular alterations and subclinical atherosclerosis to overt symptomatic CAD, ACS, and heart failure. This is robustly supported by experimental evidence that amyloid precursor protein (APP) and Aβ1-40 are critically involved in vascular inflammation, vascular and cardiac aging, and atherothrombosis. Thus, Aβ1-40 fulfills several criteria for consideration as a new biomarker for risk stratification in cardiovascular disease.

Most importantly, multiple lines of evidence clearly indicate that manipulating APP/Aβ turnover and aggregation or blocking its inflammatory reactions is feasible, potentially improving our understanding and means to simultaneously protect the brain, heart, and vessels during physiological or premature aging.

A Mechanism by Which Obesity Contributes to Hypertension

Excess fat tissue raises blood pressure. Chronically raised blood pressure, hypertension, in turn causes tissue damage to organs throughout the body. This is one of the ways in which being overweight accelerates the progression of degenerative aging and onset of age-related diseases. Researchers here report on the investigation of one of the biochemical mechanisms by which obesity can raise blood pressure; having identified it, interfering in the mechanism is the next logical step.

With obesity comes greater risk of cardiovascular disease, high blood pressure (hypertension) and stroke, among other health problems. Small arteries in our body control blood pressure. Scientists have suspected that hypertension in obesity is related to problems in endothelial cells that line these small arteries. The reasons for this, however, have been unclear – until now.

Researchers found that a protein on the membranes surrounding endothelial cells allows calcium to enter the cells and maintains normal blood pressure. Obesity, it turns out, affects this protein, called TRPV4, within tiny subsections of the cell membrane. The researchers call these faulty subsections “pathological microdomains.” Obesity, the researchers found, increases the levels of peroxynitrite-making enzymes in the microdomains containing TRPV4. Peroxynitrite silences TRPV4 and lowers calcium entry into the cells. Without the proper amount of calcium, blood pressure goes up. Targeting peroxynitrite or the enzymes that make it could be an effective way to treat and prevent high blood pressure in obesity, without the side effects that would come with trying to target TRPV4 itself.

“Historically, researchers have studied larger blood vessels that don’t control blood pressure. Because of our unique techniques, we are able to study the microdomains in very small arteries that control the blood pressure. Under healthy conditions, TRPV4 at these tiny microdomains helps maintain normal blood pressure. We, for the first time, show the sequence of events that lead to a harmful microenvironment for calcium entry through TRPV4. I think the concept of pathological microdomains is going to be very important not just for obesity-related studies but for studies of other cardiovascular disorders as well.”

Quantifying the Effects of a Healthy Lifestyle on Later Risk of Age-Related Disease

It is no big secret that maintaining a healthier lifestyle will extend the time spent free from age-related disease and generally improve the experience of later life. In this day and age, and now that the very harmful practice of smoking is waning somewhat, the practice of maintaining better health largely means resisting the siren call of excess calories and consequent excess weight. The presence of visceral fat tissue in excessive amounts accelerates the aging process. Staying slim over the course of life thus pays off down the line. If you instead choose to damage yourself in this way, the inevitable result is an earlier onset of chronic ill health, greater medical expense, and a shorter life expectancy.

The longer you lead a healthy lifestyle during midlife, the less likely you are to develop certain diseases in later life. The more time a person doesn’t smoke, eats healthy, exercises regularly, maintains healthy blood pressure, blood sugar and cholesterol levels, and maintains a normal weight, the less likely they are to develop diseases such as hypertension, diabetes, chronic kidney disease, cardiovascular disease, or to die during early adulthood.

While unhealthy lifestyle behaviors are associated with higher risks for certain diseases and death, the association of the duration in which people maintain a healthy lifestyle with the risk of disease and death had not yet been studied.

Using data from the Framingham Heart Study, researchers observed participants for approximately 16 years and assessed the development of disease or death. They found that for each five-year period that participants had intermediate or ideal cardiovascular health, they were 33 percent less likely to develop hypertension, approximately 25 percent less likely to develop diabetes, chronic kidney disease, and cardiovascular disease, and 14 percent less likely to die compared to individuals in poor cardiovascular health.

A Survey of Common Risk Factors and their Effects on Life Expectancy

The results of this epidemiological study don’t include any great surprises, but do present a convenient summary of the effect sizes of some of the commonly assessed lifestyle and environmental factors known to influence long-term health and thus life expectancy. This means smoking, level of exercise, whether or not one is overweight, undergoing sustained psychological stress, and so forth. The largest missing factor is likely degree of exposure to persistent pathogens such as cytomegalovirus, but this data is challenging to obtain across large populations, and thus isn’t present in epidemiological databases.

All of that said, the advent of practical, working rejuvenation therapies (such as senolytic treatments) will render these present variations in life expectancy largely irrelevant. In a world in which technological progress is ongoing, the pace of progress towards various means of treating aging as a medical condition will become the largest determinant of future life expectancy.

Most people want to live a long and healthy life. Choices affecting the prospects of achieving this goal are continually made by individuals themselves and by health professionals. Which amenable determinants of health and longevity should be emphasised in specific individual situations? It is well known from observational epidemiological studies that risk factors describing the sociodemographic background, lifestyles, dietary factors, life satisfaction (LS), and metabolic health predict mortality. For example, vigorous physical activity has been found to decrease the risk of death by 22% compared with no physical activity. Smoking has been found to increase the hazard by 83% and life dissatisfaction by 49%.

Comparisons between different risk factors and their impact on survival could be carried out using expected age of death (EAD) that is easier to interpret than commonly presented hazard ratios. Evidence-based decisions on how to improve the length of life, tailored to specific individual contexts, require reliable information on the EAD for different levels of these risk factors. In this study, we analyse total mortality using a model with a large number of risk factors that have previously been found to be predictors of longevity. The study assessed a otal of 38,549 participants aged 25-74 years at baseline of the National FINRISK Study between 1987 and 2007. The Primary outcome measures were register-based comprehensive mortality data from 1987 to 2014 with an average follow-up time of 16 years and 4310 deaths.

The largest influence on the EAD appeared to be a current smoker versus a never smoker as the EAD for a 30-year-old man decreased from 86.8 years, which corresponds to the reference values of the risk factors, to 82.6 years, and additionally, smoking 20 cigarettes per day decreased EAD further to 80.2 years while keeping all other risk factors at the same values. Diabetes decreased EAD almost as much to 80.3 years. Whole or full milk consumers had EAD of 84.5 years compared with 87.9 years of those consuming skimmed milk. Physically inactive men had EAD of 85.0 years whereas those with high activity had EAD of 87.4 years. Men, who found their life almost unbearable due to stress, had EAD of 84.0 years. For older men and for women the differences were similar but smaller.

BMI values below 22 and above 33, non-HDL cholesterol values below 3.6 and above 6.5, diastolic blood pressure above 85 and systolic blood pressure values below 110 and above 135 appeared to reduce the EAD when compared with the lowest risk values, but these optimal values are based on the other risk factors being at their optimal values. In practice, for example, overweight and obesity can increase blood pressure compared with normal weight, which can increase mortality.

The Proteomic Effects of Cardiopoietic Stem Cell Therapy Following Heart Attack

Cardiopoietic stem cells are used in a form of autologous mesenchymal stem cell therapy. Cells are extracted from patient bone marrow, expanded in culture, and provoked into adopting a cardiac lineage, such that they produce daughter cardiac muscle cells. Human trials have shown benefits in heart attack patients, but, as for all such therapies, it is a question as the degree to which signaling versus integration produces these benefits. Is greater regeneration the result of signaling that changes native cell behavior, followed by the death of near all of the transplanted cells, versus integration of a fraction of those transplanted cells and consequent creation of daughter cells to repair and maintain tissue?

Examining the proteomic differences before and after treatment, as is carried out in mice in this paper, doesn’t actually say all that much about which mechanism is dominant. Nonetheless, it is an interesting approach to evaluating exactly what is going on under the hood, and one that should probably be more widely applied during the development of stem cell therapies.

Cardiopoiesis leverages natural developmental cues to impart lineage engagement for enhanced cardioreparative outcome. Applied to adult stem cells, recombinant growth factor-induced cardiopoiesis disrupts latent plasticity to prime cardiovasculogenesis while maintaining a proliferative state. Supported by preclinical studies, cardiopoietic stem (CP) cell-based therapy for heart failure is undergoing clinical evaluation. While global readouts of functional and structural safety and efficacy have been the focus of exploration to date, delineation of the molecular impact of CP cells upon the recipient heart has yet to be charted.

Accordingly, proteomic profiling was here applied to characterize cardiac molecular maladaptation to ischemic cardiomyopathy, and delineate the response of diseased hearts to CP cell treatment. To this end, cells were lineage guided from human bone marrow-derived mesenchymal stem cells (MSCs), consistent with clinical trial cell sourcing. Therapeutic application of human CP cells in a xenograft model of ischemic cardiomyopathy enabled whole ventricle evaluation unachievable from clinical trial participants. This integrative approach resolved the widespread proteome remodeling seen within the infarcted tissue, and captured a non-random reversal of these disease-perturbed derangements following stem cell treatment.

Mass spectrometry resolved and quantified 3987 proteins constituting the cardiac proteome. Infarction altered 450 proteins, reduced to 283 by stem cell treatment. Notably, cell therapy non-stochastically reversed a majority of infarction-provoked changes, remediating 85% of disease-affected protein clusters. Pathway and network analysis decoded functional reorganization, distinguished by prioritization of vasculogenesis, cardiac development, organ regeneration, and differentiation. Subproteome restoration nullified adverse ischemic effects, validated by echo-/electro-cardiographic documentation of improved cardiac chamber size, reduced QT prolongation and augmented ejection fraction post-cell therapy. Collectively, cardiopoietic stem cell intervention transitioned infarcted hearts from a cardiomyopathic trajectory towards pre-disease.

Reduced Calorie Intake and Periodic Fasting Independently Contribute to the Benefits of Calorie Restriction

Researchers here make the point that calorie restriction studies in animals are also introducing a strong component of time restricted feeding, as animals tend to be fed once a day. Studies of intermittent fasting without calorie reduction have shown that this can produce a similar set of metabolic responses to a reduced calorie intake. Intermittent fasting and calorie restriction have been shown to improve health and extend healthy life spans via two overlapping sets of mechanisms, as assessed by various omics approaches. Thus the details of the approach to feeding animals any given fixed amount of calories (delivery of food per a day versus the same caloric intake split between several deliveries spaced over the day) will likely bias the results of any study.

Rodents are the most popular model to study caloric restriction (CR) in mammals. There are several ways to implement CR to rodents. One common method of food delivery is when a reduced amount of food (about 60%-80% of daily intake) is provided as a single meal once per day, usually, at the same time of the day. This type of CR induces strong food anticipation, and animals usually consume the food in a short (1-3 hr) period of time following a 21-hr period of fasting. Thus, CR is a self-imposed time-restricted (TR) feeding.

TR feeding, when an unlimited amount of food is provided for a limited time frame, significantly improves metabolic health of mice on high-fat (HF) or high-sugar diets, and this improvement in metabolism has been linked with restored or increased circadian rhythms in gene expression and signaling. Importantly, most TR studies were conducted in context of high-fat diet, obesity, or circadian rhythm disruption. Much less is known about the effect of TR on regular chow in healthy mammals.

Mealtime feeding (MTF) is another example of TR diet: 100% of daily food is provided once per day as a single meal; for unknown reasons, animals consume all food during a limited time frame in about 8-12 hr. Importantly, MTF increases longevity in mice independent of the caloric intake, suggesting that manipulation with the feeding schedule might have beneficial effects on longevity; however, the effect on lifespan is not as strong as the effect of CR. All three interventions: CR, TR, and MTF are periodic feeding/fasting diets. It was hypothesized that fasting can improve metabolism. Indeed, fasting mimicking diets such as ketogenic diet and intermittent fasting have positive effects on metabolism and, in some cases, on longevity which supports the potential importance of periodic fasting in health.

In order to understand the relative contribution of reduced food intake and periodic fasting to the health benefits of CR, we compared physiological and metabolic changes induced by CR and TR (without reduced food intake) in mice. CR significantly reduced blood glucose and insulin around the clock, improved glucose tolerance, and increased insulin sensitivity. TR reduced blood insulin and increased insulin sensitivity, but in contrast to CR, TR did not improve glucose homeostasis. Liver expression of circadian clock genes was affected by both diets while the mRNA expression of glucose metabolism genes was significantly induced by CR, and not by TR, which is in agreement with the minor effect of TR on glucose metabolism. Thus, periodic fasting contributes to some metabolic benefits of CR, but TR is metabolically different from CR. This difference might contribute to differential effects of CR and TR on longevity.

MicroRNAs miR-21 and miR-217 are Important in the Spread of Cellular Senescence via Cell Signaling

Researchers here show that miR-21 and miR-217 are important in the way in which senescent cells can encourage nearby cells to also become senescent. These microRNAs are carried between cells via extracellular vesicles, small membrane-bound packages of molecules that might constitute the bulk of cell signaling activity. The research community has of late given a lot more attention to vesicle based signaling in a number of contexts. It remains to be seen whether or not discoveries in this part of the field will lead, in the near future, to effective points of intervention in the matter of senescent cell accumulation with age or in cancer.

Cellular senescence is considered as a hallmark of ageing and a major risk factor for the development of the most common age-related diseases (ARDs). Senescent cells (SCs) are characterised by a significantly reduced replicative potential and by the acquisition of a pro-inflammatory senescence-associated secretory phenotype (SASP), which involves the paracrine induction of a senescent state in younger cells through a “bystander effect”. Since this effect fuels inflammaging – the systemic, low-grade, chronic inflammation that accompanies human ageing – it appears to be a critical step in SC accumulation during organismal ageing.

Senescence modulation by microRNAs (miRNAs) is a major senescence-related epigenetic mechanism. This has been suggested, among other findings, by the identification of discrete miRNA signatures associated with senescence in different cell types and by the fact that living cells can actively release extracellular vesicles (EVs), which contain different species and amounts of non-coding RNAs. EVs seem to reflect the molecular characteristics of their cells of origin and to modulate the phenotype of recipient cells both in a paracrine and in a systemic manner.

This study was devised to unravel the relative contribution of EVs released from senescent ECs in spreading pro-senescence signals to proliferating cells via their miRNA cargo. Based on the evidence that the in vitro replicative senescence of ECs substantially mimics the progressive age-related impairment of endothelial function described in vivo, we set out to identify the miRNAs that are differentially expressed in senescent and non-senescent human umbilical vein endothelial cells (HUVECs) and their EVs.

MicroRNA profiling of small EVs (sEVs) and large EVs demonstrated that senescent cells release a significantly greater sEV number than control cells. sEVs were enriched in miR-21-5p and miR-217, which target DNMT1 and SIRT1. Treatment of control cells with senescent cell sEVs induced a miR-21/miR-217-related impairment of DNMT1-SIRT1 expression, the reduction of proliferation markers, the acquisition of a senescent phenotype, and a partial demethylation of the locus encoding for miR-21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40-100 years showed an inverse U-shaped age-related trend for miR-21-5p, consistent with senescence-associated biomarker profiles. Our findings suggest that miR-21-5p/miR-217 carried by senescent cell sEVs spread pro-senescence signals, affecting DNA methylation and cell replication.

Failing Mitochondrial Quality Control with Age Considered in Terms of Inter-Organelle Contact Sites

The review paper here provides an interesting perspective on the interaction between mitochondria and lysosomes, looking at the mechanics of their membrane contact sites in the context of mitochondrial quality control and its age-related decline. Every cell plays host to hundreds of mitochondria, bacteria-like organelles responsible for generating adenosine triphosphate molecules to power cellular processes. Mitochondrial function declines throughout the body with age, and this appears to be largely a problem of failing quality control. The quality control processes of mitophagy identify worn and damaged mitochondria, ensuring that they are transported to a lysosome to be dismantled by enzymes. As mitophagy falters, cells become host to ever more malfunctioning or poorly functioning mitochondria, and this has profound negative effects on tissue function, particularly in energy-hungry organs such as the brain and heart.

Mitochondrial dysfunction has attracted considerable interest as a target for geroprotective interventions. Indeed, mitochondria play varied roles in a multitude of biological processes, including integration of cell death signaling and preservation of cell stemness. Albeit long considered to be standalone organelles, a great deal of evidence indicates that mitochondria interact physically and functionally with other cellular compartments via membrane contact sites and tethering molecules. In particular, mitochondria establish connections with the endosomal compartment and lysosomes. These interactions support cytosolic shuttle systems of ions and metabolites across organelles, and participate to the regulation of cellular housekeeping processes.

The mitochondrial-lysosomal axis is a major actor in mitochondrial quality control (MQC), a hierarchical network of pathways that ensure organellar homeostasis through the coordination of mitochondrial proteostasis, dynamics, biogenesis, and autophagy. While continuous cycles of fusion and fission preserve mitochondrial shape and dilute damage along the network mitochondrial hyper-fission segregates damaged or unnecessary organelles from the network. Severely damaged mitochondria are subsequently disposed via a selective form of autophagy referred to as mitophagy. Cleared mitochondria are eventually replenished via biogenesis to maintain an adequate mitochondrial pool within the cell.

Dysregulation of mitophagy and disruption of the mitochondrial-lysosomal axis coupled with abnormal EV secretion have been implicated as mechanisms in the aging process and related disease conditions. More specifically, the garbage theory of aging poses that damaged mitochondria, protein aggregates, and lipofuscin accumulate as a result of inefficient cellular quality control. The progressive accrual of intracellular “waste” further depresses cell recycling processes, thereby impinging on cell homeostasis and tissue integrity.

Functional connections between lysosomes and mitochondria have been described. Indeed, defects in either of the two organelles induce impairments in the other, indicating the existence of a mitochondrial-lysosomal axis. The genetic ablation of mitochondrial transcription factor A (TFAM), responsible for mitochondrial DNA replication, transcription, and maintenance, increases the number of lysosomes in T cells. However, lysosomal activity is impaired when deficient mitochondrial respiration and disruption of endolysosomal trafficking occur, suggesting a link between primary mitochondrial dysfunction and lysosomal storage disorders. Moreover, the restoration of lysosomal pH by lysosome-targeted nanoparticles reinstates mitophagy in pancreatic cells exposed to high concentrations of free fatty acids. These findings indicate that, at least under lipotoxic conditions, mitochondrial dysfunction develops downstream of lysosomal alkalization and that recovery of lysosomal acidity restores MQC.

Mitochondrial dysfunction, arising from failure of mitochondrial fidelity pathways, is a major mechanism driving aging and the development of age-related diseases. In this context, MQC processes may represent ideal targets for geroprotective interventions. Notably, many of the proteins involved in MQC pathways have been localized at inter-organelle interface. Such contact sites may therefore participate to some of the processes responsible for cell dyshomeostasis triggered by mitochondrial dysfunction. Hence, a deeper characterization of the structures ensuring inter – organelle crosstalk is crucial for a comprehensive assessment of mitochondrial dysfunction during aging. This knowledge, in turn, is necessary to unveil strategic pathways that may be targeted for geroprotective interventions.

Source link

Related posts

RST1 Is a FREE1 Suppressor That Negatively Regulates Vacuolar Trafficking in Arabidopsis


PAK Kinases Target Sortilin and Modulate Its Sorting [Research Article]


Combinatorial Evolution of a Terpene Synthase Gene Cluster Explains Terpene Variations in Oryza


This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More

Privacy & Cookies Policy


COVID-19 (Coronavirus) is a new illness that is having a major effect on all businesses globally LIVE COVID-19 STATISTICS FOR World